Nonalcoholic fatty liver disease (NAFLD) is associated with obesity. Because the health impact of NAFLD depends on whether or not cirrhosis occurs, our goal has been to clarify the mechanisms for NAFLD progression. In NAFLD, cirrhosis rarely develops unless steatosis progresses to steatohepatitis (NASH), but not all individuals with NASH become cirrhotic. We identified obesity-related defects in hepatic innate immunity that mediates the pathogenesis of NASH. Because a pivotal event in the transition from simple NASH to NASH with fibrosis/cirrhosis is hepatic accumulation of myofibroblastic hepatic stellate cells (MF-HSC), we developed a unifying hypothesis that might explain inter-individual differences in the susceptibility to MF-HSC accumulation during NASH. We postulate that NAFLD cirrhosis results from fibrogenic repair of hepatic injury, and HYPOTHESIZE that fibrogenic repair involves dysregulated activation of Hedgehog (Hh) signaling that disrupts normal repair-related immune responses. Our hypothesis is based on the following evidence: hepatocyte apoptosis is a key factor that distinguishes NASH from steatosis; hepatocyte death reproducibly triggers regenerative mechanisms; regeneration of chronic fatty liver damage requires expansion/differentiation of progenitors; and the latter processes are regulated by Hedgehog (Hh) ligands produced by cells that accumulate in injured livers, including MF-HSC, immature ductular cells, and NKT cells. Preliminary data suggest Hh-regulated, repair-related mechanisms promote re-accumulation of hepatic NKT cells, switching of hepatic cytokine production from a Th1-predominant to a Th2-predominant profile, and expansion of MF-HSC populations. This is probably important for NAFLD progression because NKT cell accumulation, Th2 polarization of hepatic cytokines, and MF-HSC growth promote fibrosis in other chronic liver diseases. Moreover, inherited (and acquired) differences in two systems that are known to regulate adiposity (i.e., leptin and Hedgehog) may contribute to inter-individual differences in the susceptibility to hepatic fibrosis. During the next funding period, we will determine the significance of Hh-regulated immune mechanisms that influence liver fibrosis, and evaluate if leptin and Hh signaling pathways interact to regulate fibrotic responses to liver injury. The results may expedite development of novel diagnostic tests and treatments for diverse types of obesity-related pathology, including NAFLD. PUBLIC HEALTH RELEVANCE: The results may expedite development of novel diagnostic tests and treatments for diverse types of obesity- related pathology, including NAFLD.